Shh信号通路在骨髓增生异常综合征患者骨髓干∕祖细胞中的表达及其调控机制的研究

骨髓增生异常综合征（MDS）是常见的血液系统恶性肿瘤。Hh信号通路参与肿瘤的发生，探讨Shh信号通路在MDS中的作用对阐明MDS发病机制具有重要意义。本课题拟行Shh通路在MDS骨髓干∕祖细胞中的表达，及对其功能的影响和调控机制的研究。首先分析低危和高危MDS患者骨髓CD34+和CD34-细胞中Shh、Ptch、Smo、Gli1表达，证明MDS患者CD34+细胞中存在Shh通路活化且与预后相关；第二使用外源性Shh肽、Smo和Gli1抑制剂作用CD34+和CD34-细胞，观察干预前后细胞生物活性和Shh通路中各基因及效应蛋白的变化，以及对PI3K/Akt和NF-KB通路中PI3K、P-Akt和NF-KB蛋白的影响，阐明Shh通路是通过调控PI3K/Akt和NF-KB通路维持干∕祖细胞的生存和增殖；第三Smo和Gli1抑制剂具有协同地西他滨抗癌活性的研究，为MDS治疗提供新思路。

Abstract：Myelodysplastic syndromes（MDS）is one of the most common malignant tumors in hematologic system .Abnormal activated Hedgehog(Hh)signaling pathway plays an important role in tumors,To explore the effect of Shh in MDS to clarify the pathogenesis of MDS.First,the expression of shh,ptch,smo and gli1 in both CD34+ and CD34- cells was analyzed in the low-risk and high-risk MDS patients bone marrow cells,the result proves that Shh signaling was activated in MDS stem/progenitor cells, and related with disease prognosis.Second, Exogenous Shh peptide ,Smo and Gli inhibition were respectively administered to CD34+ and CD34- cells, the changes of cell activities, the shh signaling pathway gene and associated protein expression, signaling pathway associated protein expression such as PI3K/Akt and NF-KB were performed to explore the effect of Shh signaling on the MDS stem/progenitor cells. to explore the mechanism of Shh signaling in the regulation of MDS stem/progenitor cells through action on the PI3K/Akt and NF-KB signaling.third , Experimental research on the synergistic interaction between Smo and Gli inhibition and Decitabine，It show a new therapeutic strategy towards MDS .